Development of novel and stable glucagon formulations for closed loop systems

开发用于闭环系统的新颖且稳定的胰高血糖素制剂

• 批准号: 8388789
• 负责人: Robert Hauser
• 金额: $ 28.92万
• 依托单位: BIODEL, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-19 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8388789
• 关键词: Address; Algorithms; Alpha Cell; Amino Acids; Area; Artificial Pancreas; Beta Cell; Biological; Biological Assay; Blood Glucose; Body Temperature; Carbohydrates; Cell physiology; Chemicals; Clinical; Clinical Research; Continuous Infusion; Data; Development; Devices; Diabetes Mellitus; Dose; Drug Formulations; Emergency Situation; Excipients; Exercise; Family suidae; Gel; Glucagon; Glucose; Glycogen; High Pressure Liquid Chromatography; High temperature of physical object; Hormonal; Hormones; Hour; Hypoglycemia; Infusion Pumps; Infusion procedures; Injectable; Injection of therapeutic agent; Insulin; Insulin Infusion Systems; Intramuscular Injections; Laboratories; Lead; Light; Link; Liver; Marketing; Measures; Methods; Miniature Swine; Modeling; Molecular Weight; Normal Range; Patients; Peptides; Pharmacopoeias; Phase; Physiology; Plasma; Powder dose form; Proteins; Pump; Qualifying; Quality of life; Research; Residual state; Sampling; Scientist; Simulate; Solutions; Structure of alpha Cell of islet; Structure of beta Cell of islet; Subcutaneous Injections; Syringes; System; Technology; Temperature; Testing; Time; Touch sensation; Vial device; analytical method; aqueous; blood glucose regulation; comparative; depot-insulin; design; diabetic; glucagon (rDNA); glucose sensor; glycogenolysis; improved; novel; particle; prevent; reconstitution; research study; response; subcutaneous

DESCRIPTION (provided by applicant): A device system which automatically maintain blood glucose concentrations in the normal range by dosing insulin in response to continuously sensed glucose concentration data represents a modern attempt to mechanically simulate normal beta cell physiology and solve many of the problems associated with intensive insulin therapy today, including improving the quality of life for patients with diabetes and improving glucose control. The development of such a "closed loop" artificial pancreas algorithmically linking continuous glucose sensors with insulin infusion pumps is an active area of research. Most studies with experimental artificial pancreas (AP) systems which have used insulin only have shown that hypoglycemia requiring carbohydrate administrations has not been eliminated using multiple experimental algorithms. The insulin- only approach to the artificial pancreas does not fully mimic normal physiology in that there is no ability to abort impending hypoglycemia through the use of counter-regulatory hormones. The only way for such insulin only AP system to react to declining glucose concentrations is to reduce or stop infusing subcutaneous insulin. This will not guarantee prompt termination of insulin effect in part because of residual depots of insulin in the subcutaneous space. In normal physiology, pancreatic alpha cells secrete glucagon to counter the glucose lowering effect of insulin. One of these counter-regulatory hormones is glucagon, a 29 amino acid peptide which stimulates the conversion of glycogen stored in the liver into glucose (glycogenolysis). Recent closed loop insulin studies in which glucagon is also used algorithmically to prevent impeding hypoglycemia have shown excellent glucose control with very low rates of hypoglycemia. Glucagon in its currently marketed form however is chemically and physically unstable in solution and therefore not practical for clinical development in bi-hormonal artificial pancreas systems. Biodel scientist have prepared lab formulations of aqueous glucagon at pH 7 that remain stable in solution. In this application, Biodel proposes to optimize multiple pH 7 aqueous formulations of glucagon to provide a minimum of 18 month stability under refrigerated and if possible, room temperature (25C) conditions for long-term storage requirements. We will assess whether all current US Pharmacopeia (USP) compendia methods are applicable to these formulations and we will develop suitable methods if required. We will demonstrate biological activity in a swine model and we will demonstrate that our formulation is compatible with a marketed insulin pump system at elevated temperatures for at least 9 days. PUBLIC HEALTH RELEVANCE: The full benefits of intensive insulin therapy for patients with diabetes have yet to be realized in large part because it is extremely difficult to optimize continuously variable insulin dose requirements using current technology and because of the inability to eliminate hypoglycemia. The development of closed loop artificial pancreas systems is an active area of research which promises to address the first problem; however initial studies of insulin-only systems have not shown elimination of hypoglycemia. The addition of algorithmically delivered glucagon as part of a bi-hormonal closed loop system has been shown to result in very low hypoglycemia rates. However, currently marketed formulations of glucagon are chemically and physically unstable at high temperatures and are not likely to be practical for continuous infusion through insulin pumps. In this application, Biodel proposes a strategy to develop a stable glucagon formulation suitable for continuous pump delivery.

描述（由申请人提供）：一种设备系统，该系统通过对持续感应的葡萄糖浓度数据响应响应胰岛素来自动保持血糖浓度在正常范围内，这代表了一种现代的尝试，可以机械地模拟正常的β细胞生理学并解决与当今的强化胰岛素治疗相关的许多问题，包括改善糖尿病患者的生活质量，并改善糖尿病患者的质量。这种“闭环”人工胰腺算法的开发将连续葡萄糖传感器与胰岛素输注泵联系起来是一个活跃的研究领域。大多数对使用胰岛素的实验性人工胰腺（AP）系统的研究仅表明，使用多种实验算法尚未消除需要碳水化合物施用的低血糖。人造胰腺的唯一胰岛素方法并不能完全模仿正常生理学，因为没有能力通过使用反调节激素来中止即将出现的低血糖。仅这种胰岛素AP系统对葡萄糖浓度下降的反应的唯一方法是减少或停止注入皮下胰岛素。这不能保证迅速终止胰岛素作用，部分原因是皮下空间中胰岛素的残留库。在正常的生理学中，胰腺α细胞分泌胰高血糖素以应对胰岛素的葡萄糖降低作用。这些反调节激素之一是胰高血糖素，这是一种29氨基酸肽，可刺激肝脏中存储在葡萄糖中的糖原的转化（糖基溶解）。最近的闭环胰岛素研究，其中还使用胰高血糖素以防止障碍性低血糖表现出极好的葡萄糖控制，低血糖率非常低。但是，胰高血糖素目前以化学和物理状态在溶液上是不稳定的，因此在双激素人造胰腺系统中对临床发育不切实际。生物纤维科学家已经在pH 7处制备了胰高血糖素水溶液的实验室配方，这些配方在溶液中保持稳定。在此应用中，Biodel提议优化多种pH 7的胰高血糖素水性配方，以在冷藏后至少提供18个月的稳定性，并在可能的情况下为长期存储要求提供室温（25C）条件。我们将评估所有当前的美国药物（USP）汇编方法是否适用于这些配方，如果需要，我们将开发合适的方法。我们将在猪模型中展示生物学活性，我们将证明我们的配方与在温度升高至少9天的销售胰岛素泵系统兼容。 公共卫生相关性：强化胰岛素治疗对糖尿病患者的全部好处尚未在很大程度上实现，因为很难使用当前技术优化连续可变的胰岛素剂量需求，并且由于无法消除低血糖症。闭环人工胰腺系统的开发是一个积极的研究领域，有望解决第一个问题。但是，仅胰岛素系统的初步研究尚未显示出消除低血糖症。作为双激素闭环系统的一部分，算法递送胰高血糖素的添加已显示出非常低的低血糖率。但是，目前在高温下在化学和物理上呈市场化的制剂在高温下是不稳定的，并且不太可能通过胰岛素泵连续输注。在此应用中，Biodel提出了一种策略，以开发适合连续泵输送的稳定胰高血糖素配方。